PROJECT SUMMARY The long-term career goal of the applicant is to develop an independent program of research on the neurobiological mechanisms underlying the development of Alcohol Use Disorders (AUDs), specifically those related to binge drinking. Results from the 2014 National Survey on Drug Use and Health show that 26% of adults in the US engaged in binge drinking in the past month (SAMSA 2014). Why some people ?mature out? of this behavior while others persist may be due to one?s physiological response to binge drinking. No previous study has assessed whether disrupted cortisol and neural network responses to alcohol cues may drive the compulsive alcohol consumption seen in binge drinking individuals who do not yet have an AUD. Over the course of the applicant?s career, she hopes to contribute to our understanding of the genomic, neuroendocrine, and neural mechanisms that underlie the development of AUDs. So far, she has received excellent training regarding the neurochemical and neuroanatomical substrates (from genetics to functional networks) involved in the effects of acute alcohol on the brain and in the chronic, relapsing course of severe AUDs. On this solid foundation of clinical and behavioral neuroscience, she now aims to obtain further training within the highly productive and supportive infrastructure at Yale in (1) advanced multimodal neuroimaging techniques, (2) the clinical course of hazardous drinking prior to the onset of AUDs, and (3) multilevel, mixed effects longitudinal analyses to launch a career as an independent researcher in the field of interdisciplinary, translational neuroscience research on alcoholism. Without this K99/R00 Pathway to Independence Award, the applicant will not have the protected time, training, or the resources to initiate this new direction of research. This rigorous K99 training program will help the applicant obtain a new skill set required to develop a long-term program of research which incorporates multiple interdisciplinary methods in the study of the development of AUDs. This training plan will be achieved via: 1) structured mentoring programs 2) supervised research experience, 3) formal coursework and seminars/workshops, and 4) attendance at national and international conference meetings. To further the applicant?s training with an independent research project, during the R00 phase, the applicant will recruit beer drinking, non-smoking men and women ages 21-45 (N=90, equal gender) who are either moderate drinkers or binge/heavy drinkers for a single neuroimaging and neuroendocrine assessment to determine if their real world drinking behavior in a prospective one month follow up can be predicted based upon the cortisol and neural network responses to alcohol cues. Finally, the influence of genetic variation in the FK506-binding protein 5 (FKBP5) gene, which regulates cortisol activity, on the cortisol and neural network responses to alcohol cues will be explored. This study will be the basis to build a career in understanding the neurobiological changes that drive risk of AUDs in humans.